A phase 1 dose-escalation and expansion-cohort study of the oral CDK7 inhibitor XL102 as a single-agent and in combination therapy in patients (pts) with advanced solid tumors

TPS3176 Background: XL102 is an orally bioavailable, selective, and covalent small-molecule inhibitor of cyclin-dependent kinase 7 (CDK7). CDK7 is a serine/threonine kinase that is overexpressed in multiple tumor types. CDK7 controls cell cycle progression via the phosphorylation of CDKs (1, 2, 4, and 6) and regulates transcription through phosphorylation of RNA polymerase II. XL102 induced cell death in various cancer cell lines and caused tumor regression in multiple human tumor cell line to mouse xenograft tumor models. Here, we present the study design of an ongoing phase 1 trial in pts with advanced solid tumors, including hormone receptor-positive breast cancer (HR+BC), triple-negative breast cancer (TNBC), epithelial ovarian cancer (EOC), and metastatic castration-resistant prostate cancer (mCRPC). Methods: This first-in-human, open-label, phase 1 trial (NCT04726332) consists of a dose-escalation stage and a disease-specific cohort expansion stage. In the dose-escalation stage (modified interval 3+3 design), a maximum tolerated dose and/or recommended dose (MTD/RD) of XL102 will be established (primary endpoint) for use alone (solid tumors) and then for use in combination with standard dose fulvestrant (HR+BC) or abiraterone/prednisone (mCRPC); dose escalation will require ̃36 pts for the single-agent cohort and ̃15 pts for each combination cohort. Pts enrolled in the dose-escalation stage must have an unresectable or metastatic tumor for which available therapies are intolerable, ineffective, or do not exist. Upon determining the MTD/RD for each regimen, the cohort-expansion stage will enroll according to Simon’s Two-Stage Minimax design, assuming a power of 80% and one-sided α of 15%, for single-agent XL102 (HR+BC, TNBC, EOC, and mCRPC) and XL102 in combination therapy (HR+BC and mCRPC); the expansions will enroll ̃36 pts for each single-agent cohort and ̃44 pts for each combination cohort. Pts enrolled in the expansion stage must have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), adequate organ function, and exposure to prior therapy, with specific therapy requirements based on the disease cohort. The primary endpoint of the expansion stage is objective response rate (ORR) of XL102 alone and in combination therapy as assessed by investigator per RECIST v1.1. Secondary endpoints are safety, tolerability, and pharmacokinetics. Exploratory endpoints include duration of response (DOR) and progression-free survival (PFS) as assessed by the investigator per RECIST v1.1, overall survival, and correlation of tumor and blood biomarkers with response. ORR, DOR, and PFS may also be assessed by blinded independent radiology committee in selected expansion cohorts. The study began enrolling pts in February 2021 and is ongoing. Total enrollment is estimated to be up to 298 pts. Clinical trial information: NCT04726332.